Over the last few years we have (in collaboration with Bexel Pharmaceuticals, Hayward CA) developed novel orally bio-available water-soluble drugs with potent in vitro and in vivo anti-inflammatory properties. These compounds were initially generated as derivatives of thiazolidinediones (TZD's) which are known to bind and activate the nuclear transcription factor, PPAR gamma (peroxisome proliferator-activated receptor). TZD compounds which were discovered more than 20 years ago, and was tested for its lipid lowering effects were subsequently found to be effective for the treatment of Type II diabetes. Unlike the parent TZD compounds, our novel compounds do not appear to act as ligands for PPAR gamma but instead demonstrate potent anti-inflammatory properties in vitro, without inducing any metabolic effects of TZD's. We believe, that these novel non-PPAR gamma binding TZD analogues form a new class of anti-inflammatory agents with high potential in the treatment of inflammatory disorders, including those that are autoimmune. In view of our expertise in CNS inflammatory demyelinating disorders, our proposal seeks to address the efficacy of N-PPAR gamma-TZD's in autoimmune model disease systems that have been shown to be relevant to human MS, such as experimental allergic encephalitis. While the focus of the present proposal seeks to address the relevant pre-clinical studies pertaining to inflammatory diseases of the CNS, we believe that the ultimate use of these drugs may not be limited to this disease alone but are likely to be extended to other autoimmune diseases.